We aim to prevent diabetic nephropathy by eradicating the autoimmune insulitis that causes type I diabetes mellitus, or, in hosts with established type I diabetes, we will attempt to obtain permanent tolerance to renal allografts. We will utilize novel interleukin-2 (IL-2) receptor targeted therapeis (monoclonal antibody (Mab) and chimeric molecules derived from IL-2 and certain toxins) in attempts to selectively destroy those activated T cells that are responsible for insulitis or allograft rejection in non-obese diabetic (NOD) mice. The IL-2 receptor (IL-2R), is not expressed on non-lymphoid tissues, but each and every proliferating, recently activated T-cell bears IL-2R. The IL-2R is only transiently expressed during the proliferative burst of antigen-sensitized lymphocytes; the receptor is not expressed on either resting or long term memory cells. Current immunosuppressive therapies are toxic to non-lymphoid tissues. Pan-T cell Mabs represent an important refinement in treatment; however, these agents target all T-cells for injury, broadly damaging activated and resting T lymphocyte populations alike. Consequently, we will ascertain whether administration of cytodestructive IL-2R targeted therapies, e.g. Mabs and IL-2R targeted toxins, will provide a utilitarian approach toward selective targeting of activated autoimmune or alloimmune T- cells. This treatment should abort insulitis or rejection while maintaining normal host immunity insofar as only a small population of antigen activated, T-cells are targeted. In non- diabetic hosts anti-IL-2R Mabs have proven effective in renal and cardiac organ allograft models, and (in pilot studies) preventing diabetes in NOD mice. Anti-IL-2R Mab and several hybrid toxins comprised of IL-2 and toxin will be tested in the NOD model for therapeutic efficacy.